In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system (CNS) functions. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group, namely the ionotropic receptors, forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein coupled receptors.
At present, eight different members of these mGluR are known and of these some even have sub-types. According to their sequence homology, signal transduction mechanisms and agonist selectivity, these eight receptors can be sub-divided into three sub-groups:    mGluR1 and mGluR5 belong to group I,    mGluR2 and mGluR3 belong to group II, and    mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions.
Disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Parkinson's disease, L-dopa induced dyskinesia, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain and drug dependency (Expert Opin. Ther. Patents (2002), 12, (12)). Furthermore, Expert Opin. Ther. Patents (2008), 18(2) describes the treatment of mGluR5 antagonists in situations where mGluR5 activity is exacerbated due to a specific genetic background such as Fragile-X syndrome. Fragile X patients suffer from cognitive impairment, autism spectrum disorder, aggression, seizure, anxiety, obsessive compulsive disorder, excessive tactile sensitivity, loose bowel and sensory hyper-excitability. Described in this document is also the benefit in the treatment of addiction (drugs, opioids, nicotine and alcohol), gastro-esophageal acid reflux disease (GERD), cancer and overactive bladder.
MGluR5 antagonists play also a role in situations where elevated glutamate tonus is present, for example in autism (Progress in Neuro-Psychopharmacology & Biological Psychiatry, 32, 2008, 911 and WO2008/066750).
Selective mGluR5 antagonists are especially useful for the treatment of fragile-X, depression, Parkinson and L-dopa induced dyskinesia.